The proposed studies will attempt to characterize the defect responsible for abnormal glucagon and insulin secretion in human diabetes and to define the respective metabolic consequences of glucagon excess of insulin lack. Specifically it is proposed to investigate whether abnormal alpha and beta cell function in diabetes could result from a common glucose receptor by testing the appropriateness of diabetic islet cell responses (stimulation and suppression); 1) to both hyper-and hypoglycemia; 2) to glucose anomers; 3) to nonglucose secretagogues; and 4) after sustained normoglycemia (prolonged infusion of insulin). In addition, it is planned to investigate the relative contributions of glucagon and insulin to diabetic hyperglycemia; 1) by assessing the effects on glucose tolerance and suppressing glucagon secretion with somatostatin and of infusing exogenous glucagon; 2) by quantifying changes in glucose production and utilization (measured by isotopic techniques using primed continuous infusions of tritiated glucose) during infusions of various combinations of insulin and glucagon; and 3) by characterizing the metabolic consequences of acute insulin withdrawn total pancreatectomized individuals lacking glucagon as well as insulin.